The vascular system plays an important role in maintaining normal physiological functions. For example, vascular endothelial cells form the cellular barrier functioning to regulate the migration of fluids, electrolytes, and proteins into tissues and organs. Blood vessels forming such vascular system are the necessary organs for the survival of all body forming cells and for maintaining the normal functions thereof. In particular, the incidence of such diseases that are caused by the lack of blood vessels and the loss of vascular homeostasis is increasing, which makes those diseases as an important target of the treatment.
In relation to the vascular permeability, the factors that cause malfunctioning of the endothelial barrier are complicated and are not yet understood completely, despite studies to maintain and develop the vascular permeability have been widely undergoing (Klagsbrun & Moses, Chemistry & Biology (1999), 6:R217-R224; Ferrara, Endocrine Reviews (2004), 25(4):581-611). The exact mechanism to disturb the vascular permeability has not been clearly explained yet and is only presumed to cooperate closely with other causes of various diseases including cancer, inflammatory disease such as autoimmune disease, and other pathological diseases. It is known that the vascular system related inflammation stimulates the formation of extracellular angiogenesis in relation to the disturbed vascular permeability (Kirkpatrick et al., Int. J. Microcirc. (1997), 17:231-240). For example, up-regulation of the surface adhesion molecules and their ligands, infiltration of inflammatory cells, production of cytokines, release of chemokines, oxidative stress, and activation of innate immunity can cause the vascular system related inflammation. This inflammatory response is typically related to the alteration of the vascular permeability, the transendothelial migration of leucocytes (attachment, migration, and chemotaxis), and the tissue regeneration.
According to the previous reports, angiogenesis and vascular permeability are closely related to hypoxia. In particular, the hypoxia observed in the stage of embryogenesis, the cancer tissues showing active cell proliferation, or the tissues with damaged blood vessels results in breaking a bond between the blood vessel and the endothelial cells to make the permeability unstable. Under this situation, the proliferation and migration of vascular endothelial cells are accelerated to induce angiogenesis. It is also known that various genes expressed differently by the transcription factors such as HIF-1 (hypoxia inducible factor-1) expressed under the hypoxic condition are involved in the mechanism that controls such instability of blood vessels and angiogenesis. Many of those genes are growth factors/cytokines, which are responsible for reducing the cell-cell interaction of vascular endothelial cells to increase the vascular permeability or for promoting the proliferation/migration of vascular endothelial cells to induce angiogenesis.
Abnormal angiogenesis and the regulation of vascular permeability are directly related not only to the formation of organs in the course of embryogenesis but also to many diseases from birth to adulthood. Excessive angiogenesis might cause cancer development, diabetic retinopathy, and rheumatoid arthritis, etc. On the contrary, the lack of angiogenesis causes chronic wound and ischemic cardiovascular disease, etc. The vascular permeability is also related closely to various diseases. Particularly in patients with ischemic brain disease or myocardial infarction, the high vascular permeability results in edema to cause apoptosis of neurons or cardiomyocytes. To establish a fundamental treatment method for such diseases, it is important and urgent to disclose the molecular mechanism that can regulate angiogenesis and vascular permeability. Various attempts have been made to disclose the molecular mechanism responsible for the control of angiogenesis and vascular permeability so far. As a result, it has been confirmed that VEGF (vascular endothelial growth factor) is the representative gene that regulates the vascular permeability and is over-expressed in hypoxia so as to increase the vascular permeability by binding the VEGF-receptor. The VEGF receptor is binding to VE-cadherin that regulates the cell-cell interaction of vascular endothelial cells, so that it can help VEGF to increase the vascular permeability by inducing endocytosis of VE-cadherin. Also, NO generated by VEGF/eNOS induces S-nitrosylation of β-catenin to promote the separation of VE-cadherin therefrom, resulting in the increase of vascular endothelial cell permeability (M. Rizwan et al., J. Cell Bol. (2011)193; 841-850). Thrombin, increasing vascular endothelial cell permeability, induces the generation of NO from eNOS and the activation of RhoA, which results in instability of the actin cytoskeleton and the adherent junction molecules, indicating the increase of vascular permeability (Thibeault et al., Molecular cell (2010) 39; 468-476). So, an attempt has been made to treat diabetic retinopathy caused by the increased vascular permeability by inhibiting VEGF or VEGF receptor. This attempt can also be applied to treat choroidal neovascularization, ROP (retinopathy of prematurity), and age-related macular degeneration caused by angiogenesis of immature blood vessels with high permeability (Aiello, New England Journal of Medicine (1994) 331(22):1480-1487; Adamis, American journal of Ophthalmology (1994) 118:445-450; Steinbrook, New England Journal of Medicine (2006) 355(14):1409-1412; Ferrara, American Journal of Physiol Cell Physiol (2001) 280(6):C1358-C1366). The treatment method based on the inhibition of VEGF or VEGF receptor can induce the normalization of high permeability blood vessels generated in and around a tumor, so that an anti-cancer agent can be delivered in the center of a tumor to increase the anti-cancer treatment effect (Jain, Science (2005)307 (5706): 58-62).
Unfortunately, most of the studies made so far on the regulation of angiogenesis and vascular permeability are limited to VEGF or VEGF receptors, and are focused on the development of the said gene inhibitors with asking more studies on angiogenesis and the control of vascular permeability.
Under this circumstance, the present inventors tried to screen a substance to treat vascular permeability related diseases in eye diseases. In the course of study, the present inventors confirmed that SCF (stem cell factor) increased the vascular permeability and the inhibition of the expression or phosphorylation of SCF or C-Kit (SCR receptor) reduced the vascular permeability, leading to the completion of this invention.